                1) Impact of Malaria: Malaria affects 300-500 million and kills 1-3 million individuals annually, and has an enormous economic impact, especially in sub Saharan Africa. Cumulative Gross Domestic Product of malaria endemic countries may have been reduced by 50% over the past 20 years compared with non malarious countries, and malaria was responsible for much of that loss. The World Tourist Organization reported that in 2000 there were 17.1 million international travelers to sub-Saharan Africa, 19.8 million to Central and S. America, and 46.6 million to SE Asia. It is estimated that more than 10,000 travelers from N. America, Europe, and Japan contract malaria/year. For more than 100 years during every military campaign conducted where malaria was transmitted, U.S. forces have had more casualties from malaria than from hostile fire; an estimated 12,000,000 person days lost during WW II and 1.2 million during the Vietnam conflict; at least half of these casualties were due to Pv. More than 40% of the world's population is at risk of P. vivax and there are an estimated 147 to 436 million new clinical cases annually of P. vivax malaria in the world. This is a dramatic increase over previous estimates (Mendis, K., et al., The neglected burden of Plasmodium vivax malaria. Am J. Trop Med Hyg, 2001. 64(1-2 Suppl): p. 97-106). The incidence and range of endemic malaria caused by Pv has expanded during the past 30 years and resistance to standard therapy could be widespread. Pv disease is further complicated by hypnozoites, the parasite form in the liver, creating a persistent reservoir of infection.        2) Immunity to malaria: Individuals repeatedly exposed to malaria in endemic areas develop a high degree of clinical immunity by the age of 10-15 yrs that protects them from the clinical manifestations of infection (Gunewardena, D. M., R. Carter, and K. N. Mendis, Patterns of acquired anti-malarial immunity in Sri Lanka. Mem Inst Oswaldo Cruz, 1994. 89(Suppl 2): p. 63-5.) Additionally, transfer of antibodies and cells from immune individuals and animals to susceptible hosts induces protection against malaria infections, and immunization of humans with both Plasmodium falciparum (Pf) and Pv irradiated parasites has led to sterile immunity. However, Pv has its own distinct biological properties and there is little evidence for cross-protective immunity between these Plasmodium species (Id.). In contrast, extensive data from the study of human malarial infections induced under controlled conditions indicate that immunity to each species is acquired in a species-specific manner (Collins, W. E. and G. M. Jeffery, A retrospective examination of sporozoite- and trophozoite-induced infections with Plasmodium falciparum in patients previously infected with heterologous species of Plasmodium: effect on development of parasitologic and clinical immunity. Am J Trop Med Hyg, 1999. 61(1 Suppl): p. 36-43.). It is therefore unlikely that Pv would be controlled by vaccines that may eventually be developed against Pf, indicating that Pv control will require a Pv specific vaccine. Since both parasite species coexist in most endemic areas of the world and little reduction will be observed on the overall malaria burden if a Pf vaccine alone was applied, inclusion of vaccine subunits targeting each species would be desirable in any vaccine for mass application.        3) Status of malaria vaccine development: Three approaches have been used to develop malaria subunit vaccines. The first is to create vaccines that target sporozoites as they enter the body and invade and reproduce in the liver (pre-erythrocytic stage vaccines). These have the potential to limit or prevent infection altogether. The second is to limit parasite invasion of erythrocytes and subsequent multiplication and pathological effects (asexual erythrocytic stage vaccines). Such vaccines would only limit severe disease—they would not prevent infection or mild disease. The third strategy is to prevent the spread of viable parasites to other people with transmission-blocking vaccines. These stimulate the production of antibodies that are ingested when the parasite is sucked up by a new mosquito. The antibodies destroy the parasite within the vector's gut. All 3 strategies of vaccine design are now being pursued, thanks to recent increases in funding. Current vaccine candidates in clinical trials, however, contain just one or a few proteins. According to the World Health Organization (www.who.int/vaccine research/documents/en/malaria table.pdf), there are currently more than 70 malaria vaccine candidates being studied, but only a few are at the Phase 2b (assessment of protection in the developing world). Very few III of the vaccine on the list are for P. vivax, and no P. vivax vaccine is beyond Phase I clinical trials.        a. Only one malaria protein, the P. falciparum circumsporozoite protein (PfCSP) has been repeatedly evaluated in clinical trials and shown to provide complete protection in a portion of volunteers. No other candidate protein has been shown to reproducibly protect humans in such studies. The lead candidate based on the PfCSP is called RTS,S/AS02A. In its first trial, the vaccine protected 6 out of 7 volunteers against P. falciparum challenge 3 weeks after the last immunization, and in subsequent tests it protected 40-50% of volunteers within 2-3 weeks of immunization Kester, K. E., McKinney, D. A., Tornieporth, N. et al. (Efficacy of recombinant circumsporozoite protein vaccine regimens against experimental Plasmodium falciparum malaria. J Infect Dis, 2001. 183: p. 640-647).        4) Pv Pre-erythrocytic Vaccines: The aim of a pre-erythrocytic vaccine is to prevent entry of sporozoites into hepatocytes and further development into tissue schizonts. This blocks the clinical manifestations of disease and further transmission of the parasites to the mosquito. Immunization of malaria-naive volunteers by bite of mosquitoes infected with Pf previously exposed to irradiation (15-20 kRad) consistently protects them against challenge with infectious sporozoites (Hoffman, S.L. and D.L. Doolan. Malaria vaccines-targeting infected hepatocytes. Nat Med,2000. 6(11): p. 1218-9). Protection depends on responses that arrest parasite development in the liver by direct cytolysis of infected hepatocytes, through the release of cytokines like IFNI gamma (Donlan. D.L. and S.L. Hoffman.The complexity of protective immunity against liver-stage malaria. J Immunol, 2000. 165 (3): p. 1453-62) or IL-6 (Pied. S., at al., IL-6 induced by IL-1 inhibits malaria pre-erythrocytic stages but its secretion is down-regulated by the parasite. Journal of immunology. 1992. 148(1): p. 197-201). Or through the of INOS synthase (Seguin. M.C.. et al.. induction of nitric oxide synthase protects against malaria in mice exposed to irradiated Plasmodium berahei infected mosquitoes: involvement of interferon gamma and CD8+T cells. J Exp Med. 1994.130(1): p. 353-8). Sera and cells from individuals immunized with irradiated soorozoites have allowed the identification of multiple Pfore-erythrocytic antigens and indirectly Pv proteins. PvCSP and PvSSP2. Antibodies recognize the CSP and induce a 143 precipitation reaction on the surface of live sporozoites that neutralizes sporozoite invasion into hepatocytes. The genes encoding the PfCSP and PvCSP (Arnot. D.E.. et al.. Circumsporozoite protein of Plasmodium vivax: gene cloning and characterization of the immunodominant epitope. Science. 1985. 230(4727): p. 815-8) have been cloned and sequenced. The PvCSP from the strain of Pv that was sequenced is composed of 373 amino acids and shows high similarity to those corresponding to other Plasmodia species (Sinnis. P. and V. Nussenzweig. Preventing sporozoite invasion of hepatocytes. in Malaria vaccine development. A multi151-immune response approach, S.L. Hoffman. Editor. 1996. ASM Press: Washington. D.C. p. 15-34). it is characterized by a central domain flanked by short repetitive units flanked by non-repetitive amino (N) and carboxyl (C) fragments. The flanking regions contain small stretches of highly conserved sequences designated Region I and Region II-plus that appear to represent ligand domains for invasion to the hepatocyte (Cerami, C., et al., The basolateral domain of the hepatocyte plasma membrane bears receptors for the circumsporozoite protein of Plasmodium falciparum spz. Cell, 1992. 70(6): p. 1021-33). The central PvCSP domain is composed of 19 blocks of 9 amino-acids each. There are two allelic forms present in nature, the VK210 (Pv210) or common type (GDRADGQPA) (SEQ ID NO: 11). which is present in the first PvCSP gene sequenced (Arnot. at al., supra). and the VK247 (Pv247) or variant type (ANGAGNQPG) (SEQ ID NO: 12) (Rosenberg. R.. et al.. Circumsporozoite protein heterogeneity in the human malaria parasite Plasmodium vivax. Science. 1989. 245(4921): p. 973-6). The prevalence of the Pv210 or Pv247 PvCSP sequences varies from geographic area to geographic area. but essentially all Pv parasites have one or the other of the PvCSP sequences. In Thailand, the majority of sporozoites have the Pv210 sequence. while in Colombia. the majority of sporozoites have the Pv247 sequence. Thus. an effective vaccine targeted at the PvCSP repeat region must include both repeats. Limited polymorphism has been observed in the flanking 170 regions (Mann, V.H.. et al, Sequence variation in the circumsporozoite protein gene of Plasmodium vivax appears to be regionally biased. Mol Biochem Parasita 1994. 68(1): p. 45-52). During the last decade immunological responses to the PvCSP have been studied (Arevaio-Herrera. M.. at al., Mapping and comparison of the B-cell epitopes recognized on the Plasmodium vivax circumsporozoite protein by immune Colombians and immunized Aotus monkeys. Ann Trop Med Parasitoi, 1998. 92(5): p. 539-51), B-cell epitopes have been found throughout the whole sequence (Id.) and both VK210and VK247 are recognized by sera of immune individuals from different malaria endemic areas (See. e.g.. Machado. R.L. and M.M. Povoa, Distribution of Plasmodium vivax variants (VK210. VK247 and Pv-like) in three endemic areas of the Amazon region of Brazil and their correlation with chloroquine treatment. Trans R Soc Trop Med Hvg, 2000. 94(4): p. 377-81). The VK210 variant contains the PAGDR (SEQ ID NO: 13) sequence. which is recognized in individuals from malaria endemic areas as well as by a monoclonal antibody that protects Saimiri monkeys from challenge with Pv sporozoites. Multiple T helper epitopes recognized in the context of a number of MHC class II haplotypes have also been mapped. One of these epitopes was broadly recognized in individuals from malaria endemic areas of Colombia carrying different class II haplotypes. More recently. using nona- or deca-peptides containing MHC class I binding motifs. peptides capable of stimulating human CD8+T cells from HLA-A*0201 individuals to produce IFN gamma in vitro were identified.        5) Immunization of Saimiri species with PvCSP recombinant proteins (Collins W E, et al. Immunization of Saimiri sciureus boliviensis with rec vaccines based on the circumsporozoite protein of Plasmodium vivax. Am J Trop Med. Hyg. 1989 May; 40(5):455-64), and immunization of Saimiri sp. with a PvCSP synthetic peptide vaccine (Collins W E, et al. Protective immunity induced in squirrel monkeys with a multiple antigen construct against the circumsporozoite protein of Plasmodium vivax. Am J Trop Med. Hyg. 1997 February; 56(2):200-10) have been reported. In the first study there was essentially no protection against sporozoite challenge. In the second study 11 of 26 monkeys were protected against sporozoite challenge, but there was no control group, and there have not been any follow up studies reported. Immunological characterization of the PvCSP has been conducted, and the vaccine potential of 3 long synthetic peptides encompassing the N-terminal (peptide N; position 20-96) and the C-terminal regions (peptide C; position 301-372) as well as a third peptide (peptide R) consisting of 3 copies of the Pv210 9 amino acid repeat region synthesized with the universal T cell epitope P30 (Panina-Bordignon, P., et al., Universally immunogenic T cell epitopes: promiscuous binding to human MHC class II and promiscuous recognition by T cells. Eur J Immunol, 1989. 19(12): p. 2237-42; Valmori, D., et al., Use of human universally antigenic tetanus toxin T cell epitopes as carriers for human vaccination. J. Immunol, 1992. 149(2): p. 717-21 have been assessed individually in primates with. Montanide ISA 720 as adjuvant. While these peptides/adjuvant preparations are safe well tolerated and immunogenic in humans, limitations on manufacturing long synthetic peptides, and on mixing peptides in a single vaccine, make these compositions poor candidates as human vaccines.        